Pyrazole derivatives as sigma receptor inhibitors

ABSTRACT

The invention relates to compounds of formula I 
     
       
         
         
             
             
         
       
         
         
           
             having pharmacological activity towards the sigma receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which the sigma receptor is involved.

FIELD OF THE INVENTION

The present invention relates to compounds having pharmacologicalactivity towards the sigma (σ) receptor, and more particularly to somepyrazole derivatives, to processes of preparation of such compounds, topharmaceutical compositions comprising them, and to their use in therapyand prophylaxis, in particular for the treatment of psychosis.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of proteins and otherbiomolecules associated with target diseases. One important class ofthese proteins is the sigma (σ) receptor, a cell surface receptor of thecentral nervous system (CNS) which may be related to the dysphoric,hallucinogenic and cardiac stimulant effects of opioids. From studies ofthe biology and function of sigma receptors, evidence has been presentedthat sigma receptor ligands may be useful in the treatment of psychosisand movement disorders such as dystonia and tardive dyskinesia, andmotor disturbances associated with Huntington's chorea or Tourette'ssyndrome and in Parkinson's disease (Walker, J. M. et al,Pharmacological Reviews, 1990, 42, 355). It has been reported that theknown sigma receptor ligand rimcazole clinically shows effects in thetreatment of psychosis (Snyder, S. H., Largent, B. L. J. Neuropsychiatry1989, 1, 7). The sigma binding sites have preferential affinity for thedextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF10047, (+)cyclazocine, and (+)pentazocine and also for some narcolepticssuch as haloperidol.

The sigma receptor has at least two subtypes, which may be discriminatedby stereoselective isomers of these pharmacoactive drugs. SKF 10047 hasnanomolar affinity for the sigma 1 (σ-1) site, and has micromolaraffinity for the sigma (σ-2) site. Haloperidol has similar affinitiesfor both subtypes. Endogenous sigma ligands are not known, althoughprogesterone has been suggested to be one of them. Possiblesigma-site-mediated drug effects include modulation of glutamatereceptor function, neurotransmitter response, neuroprotection, behavior,and cognition (Quirion, R. et al. Trends Pharmacol. Sci., 1992,13:85-86). Most studies have implied that sigma binding sites(receptors) are plasmalemmal elements of the signal transductioncascade. Drugs reported to be selective sigma ligands have beenevaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad. Sci.,1996, 93:8072-8077). The existence of sigma receptors in the CNS, immuneand endocrine systems have suggested a likelihood that it may serve aslink between the three systems.

In view of the potential therapeutic applications of agonists orantagonists of the sigma receptor, a great effort has been directed tofind selective ligands. Thus, the prior art discloses different sigmareceptor ligands.

International Patent Application WO 91/09594 generically describes abroad class of sigma receptor ligands some of which are4-phenylpiperidine, -tetrahydro-pyridine or -piperazine compounds havingan optionally substituted aryl or heteroaryl, alkyl, alkenyl, alkynyl,alkoxy or alkoxyalkyl substituent on the ring N-atom. The terms aryl andheteroaryl are defined by mention of a number of such substituents.

European patent application EP 0 414 289 A1 generically discloses aclass of 1,2,3,4-tetrahydro-spiro[naphthalene-1,4′-piperidine] and1,4-dihydro-spiro[naphthalene-1,4′-piperidine] derivatives substitutedat the piperidine N-atom with a hydrocarbon group alleged to haveselective sigma receptor antagonistic activity. The term hydrocarbon, asdefined in said patent, covers all possible straight chained, cyclic,heterocyclic, etc. groups. However, only compounds having benzyl,phenethyl, cycloalkylmethyl, furyl- or thienylmethyl or lower alkyl oralkenyl as the hydrocarbon substituent at the piperidine nitrogen atomare specifically disclosed. The compounds are stated to displacetritiated di-tolyl guanidine (DTG) from sigma sites with potenciesbetter than 200 nM.1′-benzyl-1,2,3,4-tetrahydro-spiro[naphthalene-1,4′-piperidine] ismentioned as a particularly preferred compound.

European patent application EP 0 445 974 A2 generically describes thecorresponding spiro[indane-1,4′-piperidine] andspiro[benzocycloheptene-5,4′-piperidine] derivatives. Again thecompounds are only stated to displace tritiated di-tolyl guanidine (DTG)from sigma sites with potencies better than 200 nM.

European patent Application EPO 431 943 A relates to a further extremelybroad class of spiropiperidine compounds substituted at the piperidineN-atom and claimed to be useful as antiarrhythmics and for impairedcardiac pump function. The said application exemplifies severalcompounds, the majority of which contain an oxo and/or a sulfonylaminosubstituent in the spiro cyclic ring system. Of the remainder compounds,the main part has another polar substituent attached to the spironucleus and/or they have some polar substituents in the substituent onthe piperidine N-atom. No suggestion or indication of effect of thecompounds on the sigma receptor is given.

Patent applications EP 518 805 A and WO 02/102387 describe sigmareceptor ligands having piperidine or spiropiperidine structures.

With regard to the chemical structure of the compounds described in thepresent patent application, there are some documents in the prior artwhich disclose pyrazole derivatives characterized, among other things,for being substituted by amino alkoxy groups in different positions ofthe pyrazole group.

U.S. Pat. No. 4,337,263 discloses 1-aryl-4-arylsulphonyl-3-aminopropoxy-1H-pyrazoles, wherein the amino group can be constituted by anN-cycle group as morpholine, piperidine or pyrrolidine group. They areused as hypolipemiant or hypocholesteroleminant agents.

Patent FR 2301250 describes similar compounds as those mentioned above,such as 1,4-diaryl-3-aminoalcoxy pyrazoles, wherein the amino groupcomprises pyrrolidine, piperidine, hydroxypiperidine, morpholine orpiperazine derivatives.

Patent Application US2003/0144309 refers to pyrazoles with their 3position substituted by a dimethylaminoethoxy group and present in their4 position a pirimidine group. They are used as inhibitors of JNK3, Lckor Src kinase activity.

International patent Application WO 02/092573 describes substitutedpirazole compounds as inhibitors of SRC and other protein kinases.

International patent Application WO 2004/017961 discloses pyrazolcompounds wherein the 3 position is substituted by an alcoxy groupdirectly bounded to a cyclic amide, which are used for therapeuticallytreating and/or preventing a sex hormone related condition in a patient.

U.S. Pat. No. 6,492,529 describes pyrazole derivatives which are usedfor the treatment of inflammatory diseases. These compounds present inthe 5 position a urea group, linked in some cases to a morpholine ethoxygroup.

International patent Application WO 04/016592 refers to pyrazolecompounds for inhibiting protein prenylation which comprises in the 5position, among others, an alcoxy group directly bonded to a cyclicamide.

However, none of these documents suggests the effect of these compoundson the sigma receptor.

There is still a need to find compounds that have pharmacologicalactivity towards the sigma receptor, being both effective and selective,and having good “drugability” properties, i.e. good pharmaceuticalproperties related to administration, distribution, metabolism andexcretion.

SUMMARY OF THE INVENTION

We have now found a family of structurally distinct pyrazol derivativeswhich are particularly selective inhibitors of the sigma receptor. Thecompounds present a pyrazol group which are characterized by thesubstitution at position 3 by an alkoxy group directly bounded to anitrogen.

The invention is directed to a compound of the formula I:

wherein

-   -   R₁ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        alkenyl, substituted or unsubstituted arylalkyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,        —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or        halogen;    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;    -   Y is selected from substituted or unsubstituted phenyl or        naphtyl; substituted or unsubstituted, branched or linear        C₁₋₆-alkyl; substituted or unsubstituted C₃₋₈-cycloalkyl;        substituted or unsubstituted heterocyclyl;    -   X is selected from:        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,            -   with            -   Het being NH, S or O,            -   —CHR_(x)— being

-   -   -   -    with            -   R₅ and R₆, identical or different, represent a hydrogen                atom; an optionally substituted C₁₋₄ alkyl group; an                optionally substituted aryl group; an optionally                substituted heteroaryl group; a C₁₋₄ alkoxy group; a                benzyl group; a phenethyl group;            -   or            -   form, together with their bridging nitrogen atom, an                optionally substituted heteroaryl group which is                optionally condensed to other, optionally at least one                heteroatom containing mono- or polycyclic ring system                which is optionally at least mono-substituted;

    -   or

    -   X is selected from:        -   —CH₂—CH₂—CH₂—NR_(x)—,        -   —CH₂—CH₂—NR_(x)—CH₂—,        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   —CH₂—CH₂—NR_(x)—,        -   —CH₂—NR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,        -   —CH₂—NR_(x)—,            -   with            -   Het being NH, S or O,            -   R_(x) being a —(C═O)—R¹⁰; or a —(C═O)—O—R¹¹ group; with            -   R¹⁰ and R¹¹ independently represent a hydrogen atom; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl group; an optionally at                least mono-substituted aryl group; an optionally at                least mono-substituted heteroaryl group; an optionally                at least mono-substituted, optionally at least one                heteroatom as ring member containing cycloalkyl group; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl-aryl group; a saturated or                unsaturated, optionally at least mono-substituted C₁₋₆                alkyl-heteroaryl group; a saturated or unsaturated,                optionally at least mono-substituted C₁₋₆                alkyl-cycloalkyl group wherein the cycloalkyl group                contains optionally at least one heteroatom as ring                member;

    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;

    -   t is 1, 2 or 3;

    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        or halogen;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In a preferred embodiment the compound according to the invention is acompound of the formula IB:

wherein

-   -   R₁ is selected from the group formed by hydrogen; substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted aromatic heterocyclyl, substituted        or unsubstituted heterocyclyl, substituted or unsubstituted        heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,        —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2, —N═CR₈R₉ or halogen,    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;    -   R₃ and R₄ are independently selected from the group formed by        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO2, —N═CR₈R₉, or halogen, or together they form a        fused ring system,    -   X is selected from:        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,            -   with            -   Het being NH, S or O,            -   —CHR_(x)— being

-   -   -   -    and            -   R₅ and R₆, identical or different, represent a hydrogen                atom; an optionally substituted C₁₋₄ alkyl group; an                optionally substituted aryl group; an optionally                substituted heteroaryl group; a C₁₋₄ alkoxy group; a                benzyl group; a phenethyl group;            -   or            -   form, together with their bridging nitrogen atom, an                optionally substituted heteroaryl group which is                optionally condensed to other, optionally at least one                heteroatom containing mono- or polycyclic ring system                which is optionally at least mono-substituted;

    -   or

    -   X is selected from:        -   —CH₂—CH₂—CH₂—NR_(x)—,        -   —CH₂—CH₂—NR_(x)—CH₂—,        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   —CH₂—CH₂—NR_(x)—,        -   —CH₂—NR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,        -   —CH₂—NR_(x)—,            -   with            -   Het being NH, S or O,            -   R_(x) being a —(C═O)—R¹⁰; or a —(C═O)—O—R¹¹ group; with            -   R¹⁰ and R¹¹ independently represent a hydrogen atom; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl group; an optionally at                least mono-substituted aryl group; an optionally at                least mono-substituted heteroaryl group; an optionally                at least mono-substituted, optionally at least one                heteroatom as ring member containing cycloalkyl group; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl-aryl group; a saturated or                unsaturated, optionally at least mono-substituted C₁₋₆                alkyl-heteroaryl group; a saturated or unsaturated,                optionally at least mono-substituted C₁₋₆                alkyl-cycloalkyl group wherein the cycloalkyl group                contains optionally at least one heteroatom as ring                member;

    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;

    -   t is 1, 2 or 3;

    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        or halogen;

optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

Another preferred embodiment of Group A according to the invention is acompound of the formula I:

-   -   wherein    -   R₁ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        alkenyl, substituted or unsubstituted arylalkyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,        —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or        halogen;    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;    -   Y is selected from substituted or unsubstituted phenyl or        naphtyl; substituted or unsubstituted, branched or linear        C₁₋₆-alkyl; substituted or unsubstituted C₃₋₈-cycloalkyl;        substituted or unsubstituted heterocyclyl;    -   X is selected from:        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,            -   with            -   Het being NH, S or O,            -   —CHR_(x)— being

-   -   -   -    with            -   R₅ and R₆, identical or different, represent a hydrogen                atom; an optionally substituted C₁₋₄ alkyl group; an                optionally substituted aryl group; an optionally                substituted heteroaryl group; a C₁₋₄ alkoxy group; a                benzyl group; a phenethyl group;            -   or            -   form, together with their bridging nitrogen atom, an                optionally substituted heteroaryl group which is                optionally condensed to other, optionally at least one                heteroatom containing mono- or polycyclic ring system                which is optionally at least mono-substituted;

    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;

    -   t is 1, 2 or 3;

    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        or halogen;

    -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.        Another preferred embodiment of Group A according to the        invention is a compound of the formula IB:

wherein

-   -   R₁ is selected from the group formed by hydrogen; substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted aromatic heterocyclyl, substituted        or unsubstituted heterocyclyl, substituted or unsubstituted        heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,        —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2, —N═CR₈R₉ or halogen,    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;    -   R₃ and R₄ are independently selected from the group formed by        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO2, —N═CR₈R₉, or halogen, or together they form a        fused ring system,    -   X is selected from:        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,            -   with            -   Het being NH, S or O,            -   —CHR_(x)— being

-   -   -   -    with            -   R₅ and R₆, identical or different, represent a hydrogen                atom; an optionally substituted C₁₋₄ alkyl group; an                optionally substituted aryl group; an optionally                substituted heteroaryl group; a C₁₋₄ alkoxy group; a                benzyl group; a phenethyl group;            -   or            -   form, together with their bridging nitrogen atom, an                optionally substituted heteroaryl group which is                optionally condensed to other, optionally at least one                heteroatom containing mono- or polycyclic ring system                which is optionally at least mono-substituted;

    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;

    -   t is 1, 2 or 3;

    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        or halogen;

    -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.        Another preferred embodiment of Group B according to the        invention is a compound of the

-   -   wherein    -   R₁ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        alkenyl, substituted or unsubstituted arylalkyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,        —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or        halogen;    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;    -   Y is selected from substituted or unsubstituted phenyl or        naphtyl; substituted or unsubstituted, branched or linear        C₁₋₆-alkyl; substituted or unsubstituted C₃₋₈-cycloalkyl;        substituted or unsubstituted heterocyclyl;    -   X is selected from:        -   —CH₂—CH₂—CH₂—NR_(x)—,        -   —CH₂—CH₂—NR_(x)—CH₂—,        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   —CH₂—CH₂—NR_(x)—,        -   —CH₂—NR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,        -   —CH₂—NR_(x)—,            -   with            -   Het being NH, S or O,            -   R_(x) being a —(C═O)—R¹⁰; or a —(C═O)—O—R¹¹ group;            -   and            -   R¹⁰ and R¹¹ independently represent a hydrogen atom; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl group; an optionally at                least mono-substituted aryl group; an optionally at                least mono-substituted heteroaryl group; an optionally                at least mono-substituted, optionally at least one                heteroatom as ring member containing cycloalkyl group; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl-aryl group; a saturated or                unsaturated, optionally at least mono-substituted C₁₋₆                alkyl-heteroaryl group; a saturated or unsaturated,                optionally at least mono-substituted C₁₋₆                alkyl-cycloalkyl group wherein the cycloalkyl group                contains optionally at least one heteroatom as ring                member;    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;    -   t is 1, 2 or 3;    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        or halogen;    -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.        Another preferred embodiment of Group A according to the        invention is a compound of the formula IB:

wherein

-   -   R₁ is selected from the group formed by hydrogen; substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted aromatic heterocyclyl, substituted        or unsubstituted heterocyclyl, substituted or unsubstituted        heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,        —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2, —N═CR₈R₉ or halogen,    -   R₂ is selected from the group formed by hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;    -   R₃ and R₄ are independently selected from the group formed by        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,        —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉,        —NR₈C(O)R₉, —NO2, —N═CR₈R₉, or halogen, or together they form a        fused ring system,    -   X is selected from:        -   —CH₂—CH₂—CH₂—NR_(x)—,        -   —CH₂—CH₂—NR_(x)—CH₂—,        -   —CH₂—CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—CH₂—,        -   —CH₂-Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CH₂—CHR_(x)—,        -   —CH₂—CH₂-Het-CHR_(x)—,        -   —CH₂-Het-CHR_(x)—,        -   —CH₂—CHR_(x)-Het-,        -   -Het-CH₂—CHR_(x)—,        -   —CH₂—CH₂—CHR_(x)—,        -   —CH₂—CHR_(x)—CH₂—,        -   —CH₂—CH₂—NR_(x)—,        -   —CH₂—NR_(x)—CH₂—,        -   -Het-CHR_(x)—,        -   —CH₂—CHR_(x)—,        -   —CH₂—NR_(x)—,            -   with            -   Het being NH, S or O,            -   R_(x) being a —(C═O)—R¹⁰; or a —(C═O)—O—R¹¹ group;            -   and            -   R¹⁰ and R¹¹ independently represent a hydrogen atom; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl group; an optionally at                least mono-substituted aryl group; an optionally at                least mono-substituted heteroaryl group; an optionally                at least mono-substituted, optionally at least one                heteroatom as ring member containing cycloalkyl group; a                saturated or unsaturated, optionally at least                mono-substituted C₁₋₆ alkyl-aryl group; a saturated or                unsaturated, optionally at least mono-substituted C₁₋₆                alkyl-heteroaryl group; a saturated or unsaturated,                optionally at least mono-substituted C₁₋₆                alkyl-cycloalkyl group wherein the cycloalkyl group                contains optionally at least one heteroatom as ring                member;    -   n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;    -   t is 1, 2 or 3;    -   R₈ and R₉ are each independently selected from hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocyclyl,        or halogen;        optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.        In one embodiment R₁ of formulas I or IB is selected from H,        halogen, —COR₈, or substituted or unsubstituted alkyl,        preferably it is selected from H, Cl, methyl or acetyl.        In one embodiment R₁ of formulas I or IB is hydrogen.        In one embodiment R₂ of formulas I or IB is H, aryl, C(O)OR₈ or        alkyl, preferably methyl, iso-propyl, phenyl, C(O)O—C₂H₅ or H.        In one embodiment R₃ and R₄ of formula IB are situated in the        meta and para positions of the phenyl group.        In one embodiment R₃ and R₄ of formula IB are independently        selected from halogen, hydrogen, alkoxy, or substituted or        unsubstituted alkyl, more preferably selected from hydrogen,        halogen, Cl, methoxy or haloalkyl.        In one embodiment R₃ and R₄ of formula IB together form a fused        ring system, especially a fused ring system leading with the        phenyl to form a naphthyl-radical.        In one embodiment n of formula I or IB is selected from 2, 3, 4.        In one embodiment of Group A X of formulas I or IB is selected        from    -   —CH₂—CH₂—CHR_(x)—,    -   —CH₂—CHR_(x)—CH₂—,    -   —CH₂—CHR_(x)—.        In one embodiment of Group A R₅ and R₆ of formula I or IB are        selected from hydrogen or alkyl    -   or    -   form, together with their bridging nitrogen atom, an optionally        substituted heteroaryl group which is optionally condensed to        other, optionally at least one heteroatom containing mono- or        polycyclic ring system which is optionally at least        mono-substituted, especially an indazole or an 1H-indazole.        In one embodiment of Group A the compound is selected from

-   3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine,

-   3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine    oxalate,

-   1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine,

-   1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine    oxalate,    -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or another        corresponding salt thereof, or a corresponding solvate thereof.        In one embodiment of Group B X of formulas I or IB is selected        from    -   —CH₂—CH₂—NR_(x)—,    -   —CH₂—NR_(x)—CH₂—,    -   —CH₂—NR_(x)—;    -   preferably    -   —CH₂—NR_(x)—CH₂—.        In one embodiment of Group B R₁₀ and R₁₁ of formulas I or IB are        independently selected from hydrogen or alkyl.        In one embodiment of Group B the compound is selected from

-   1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine,

-   1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine    oxalate,

-   1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone,

-   1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone    oxalate,

-   1-{1-[2-(1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}ethanone,

-   1-{1-[2-(1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}ethanone    oxalate,

-   1-{4-[2-(1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl]piperazin-1-yl}ethanone,

-   1-{4-[2-(1-(3,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy)ethyl]pipera-zin-1-yl}ethanone    oxalate

-   1-(1-[2-{1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy}ethyl]piperi-din-4-yl)ethanone,

-   1-(1-[2-{1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy}ethyl]piperi-din-4-yl)ethanone    oxalate,

-   1-(1-(2-(1-(4-Chloro-phenyl)-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanone,

-   1-(1-(2-(1-(4-Chloro-phenyl)-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanone    oxalate,

-   1-(1-(2-(1-(3,4-Dichlo-rophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanone,

-   1-(1-(2-(1-(3,4-Dichlo-rophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanone    oxalate,

-   1-(4-(4-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)butyl)piperazin-1-yl)ethanone,

-   1-(4-(4-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)butyl)piperazin-1-yl)ethanone    oxalate,

-   1-(4-(2-(1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone,

-   1-(4-(2-(1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone    oxalate;

-   1-(4-(2-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone,

-   1-(4-(2-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone    oxalate,

-   1-(4-{4-[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-3-yloxy]-butyl}-piperazin-1-yl)-ethanone

-   1-(4-{4-[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-3-yloxy]-butyl}-piperazin-1-yl)-ethanone    oxalate;    -   optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or another        corresponding salt thereof, or a corresponding solvate thereof.

Another aspect the invention is directed to a process for thepreparation of a compound of formula (I) or a salt, isomer or solvatethereof.

In another aspect the invention is directed to a pharmaceuticalcomposition which comprises a compound as above defined or apharmaceutically acceptable salt, enantiomer, prodrug or solvatethereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

In a further aspect the invention is directed to the use of a compoundof formula I or IB for the treatment or prophylaxis of a sigma receptormediated disease or condition.

In another preferred embodiment the compounds as above defined are usedin the manufacture of a medicament for the treatment of diarrhoea,lipoprotein disorders, metabolic syndrome, treatment of elevatedtriglyceride levels, chylomicronemia, hyperlipoproteinemia;hyperlipidemia, especially mixed hyperlipidemia; hypercholesterolemia,dysbetalipoproteinemia, hypertriglyceridemia including both the sporadicand familial disorder (inherited hypertriglyceridemia), migraine,obesity, arthritis, hypertension, arrhythmia, ulcer, learning, memoryand attention deficits, cognition disorders, neurodegenerative diseases,demyelinating diseases, addiction to drugs and chemical substancesincluding cocaine, amphetamine, ethanol and nicotine, tardivediskinesia, ischemic stroke, epilepsy, stroke, depression, stress,psychotic condition, schizophrenia; inflammation, autoimmune diseases orcancer; disorders of food ingestion, the regulation of appetite, for thereduction, increase or maintenance of body weight, for the prophylaxisand/or treatment of obesity, bulimia, anorexia, cachexia or type IIdiabetes, preferably type II diabetes caused by obesity; or to the useas pharmacological tool, as anxiolytic or as immunosuppressant.

In a more preferred embodiment the medicament is for the treatment ofpain, especially neuropathic pain, inflammatory pain or other painconditions, allodynia and/or hyperalgesia, especially mechanicalallodynia.

The above mentioned preferences and embodiments can be combined to givefurther preferred compounds or uses.

DETAILED DESCRIPTION OF THE INVENTION

The typical compounds of this invention effectively and selectivelyinhibit the sigma receptor.

In the present description the following terms have the meaningindicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting of carbon and hydrogen atoms, containing no saturation,having one to eight carbon atoms, and which is attached to the rest ofthe molecule by a single bond, e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionallysubstituted by one or more substituents such as a aryl, halo, hydroxy,alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro,mercapto, alkylthio, etc. If substituted by aryl we have an “Aralkyl”radical, such as benzyl and phenethyl.

“Alkenyl” refers to an alkyl radical having at least 2 C atoms andhaving one or more unsaturated bonds.

“Cycloalkyl” refers to a stable 3- to 10-membered monocyclic or bicyclicradical which is saturated or partially saturated, and which consistsolely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl.Unless otherwise stated specifically in the specification, theterm“cycloalkyl” is meant to include cycloalkyl radicals which areoptionally substituted by one or more substituents such as alkyl, halo,hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.

“Aryl” refers to single and multiple ring radicals, including multiplering radicals that contain separate and/or fused aryl groups. Typicalaryl groups contain from 1 to 3 separated or fused rings and from 6 toabout 18 carbon ring atoms, such as phenyl, naphthyl, indenyl,fenanthryl or anthracyl radical. The aryl radical may be optionallysubstituted by one or more substituents such as hydroxy, mercapto, halo,alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino,aminoalkyl, acyl, alkoxycarbonyl, etc.

“Heterocyclyl” refers to a stable 3- to 15 membered ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, preferably a 4- to8-membered ring with one or more heteroatoms, more preferably a 5- or6-membered ring with one or more heteroatoms. It may be aromatic or notaromatic. For the purposes of this invention, the heterocycle may be amonocyclic, bicyclic or tricyclic ring system, which may include fusedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidised; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated or aromatic. Examples of such heterocycles include,but are not limited to, azepines, benzimidazole, benzothiazole, furan,isothiazole, imidazole, indole, piperidine, piperazine, purine,quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole,pyrazole, oxazole, isoxazole, triazole, imidazole, etc.“Heterocyclylalkyl” refers accordingly to a “Heterocyclyl” radical beingconnected via an “Alkyl” chain.

“Alkoxy” refers to a radical of the formula —ORa where Ra is an alkylradical as defined above, e.g., methoxy, ethoxy, propoxy, etc.

“Amino” refers to a radical of the formula —NH2, —NHRa or —NRaRb,optionally quaternized.

“Halo” or “hal” refers to halogen such as bromo, chloro, iodo or fluoro.

References herein to substituted groups in the compounds of the presentinvention refer to the specified moiety that may be substituted at oneor more available positions by one or more suitable groups, e.g.,halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro;amino, azido; esters, e.g. esters of carbonic acid etc.; (C═O) groupssuch as e.g. acetyl, propanoyl etc.; alkyl groups including those groupshaving 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms andmore preferably 1-3 carbon atoms; alkenyl and alkynyl groups includinggroups having one or more unsaturated linkages and from 2 to about 12carbon or from 2 to about 6 carbon atoms; alkoxy groups having one ormore oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6carbon atoms; aryloxy such as phenoxy; alkylthio groups including thosemoieties having one or more thioether linkages and from 1 to about 12carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groupsincluding those moieties having one or more sulfinyl linkages and from 1to about 12 carbon atoms or from 1 to about 6 carbon atoms;alkylsulfonyl groups including those moieties having one or moresulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about6 carbon atoms; aminoalkyl groups such as groups having one or more Natoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbonatoms; carbocylic aryl having 6 or more carbons, particularly phenyl ornaphthyl and aralkyl such as benzyl. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group, and each substitution isindependent of the other.

In a preferred embodiment particular individual compounds listed belowand falling under formula (I) are excluded/disclaimed from theinvention:

-   Ex1:    3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine;-   Ex2:    1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine;    optionally in form of one of the stereoisomers, preferably    enantiomers or diastereomers, a racemate or in form of a mixture of    at least two of the stereoisomers, preferably enantiomers and/or    diastereomers, in any mixing ratio, or a corresponding salt thereof,    or a corresponding solvate thereof.

Unless otherwise stated, the compounds of the invention are also meantto include compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonor ¹⁵N-enriched nitrogen are within the scope of this invention.

The term “pharmaceutically acceptable salts, solvates, prodrugs” refersto any pharmaceutically acceptable salt, ester, solvate, or any othercompound which, upon administration to the recipient is capable ofproviding (directly or indirectly) a compound as described herein.However, it will be appreciated that non-pharmaceutically acceptablesalts also fall within the scope of the invention since those may beuseful in the preparation of pharmaceutically acceptable salts. Thepreparation of salts, prodrugs and derivatives can be carried out bymethods known in the art.

For instance, pharmaceutically acceptable salts of compounds providedherein are synthesized from the parent compound which contains a basicor acidic moiety by conventional chemical methods. Generally, such saltsare, for example, prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent or in a mixture of the two.Generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol or acetonitrile are preferred. Examples of the acid additionsalts include mineral acid addition salts such as, for example,hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate,and organic acid addition salts such as, for example, acetate, maleate,fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate,methanesulphonate and p-toluenesulphonate. Examples of the alkaliaddition salts include inorganic salts such as, for example, sodium,potassium, calcium, ammonium, magnesium, aluminium and lithium salts,and organic alkali salts such as, for example, ethylenediamine,ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine andbasic aminoacids salts.

Particularly favored derivatives or prodrugs are those that increase thebioavailability of the compounds of this invention when such compoundsare administered to a patient (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species.

Any compound that is a prodrug of a compound of formula (I) or (IB) iswithin the scope of the invention. The term “prodrug” is used in itsbroadest sense and encompasses those derivatives that are converted invivo to the compounds of the invention. Such derivatives would readilyoccur to those skilled in the art, and include, depending on thefunctional groups present in the molecule and without limitation, thefollowing derivatives of the present compounds: esters, amino acidesters, phosphate esters, metal salts sulfonate esters, carbamates, andamides. Examples of well known methods of producing a prodrug of a givenacting compound are known to those skilled in the art and can be founde.g. in Krogsgaard-Larsen et al. “Textbook of Drug design and Discovery”Taylor & Francis (April 2002).

The compounds of the invention may be in crystalline form either as freecompounds or as solvates and it is intended that both forms are withinthe scope of the present invention. Methods of solvation are generallyknown within the art. Suitable solvates are pharmaceutically acceptablesolvates. In a particular embodiment the solvate is a hydrate.

The compounds of formula (I) or (IB) or their salts or solvates arepreferably in pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels. Purity levels for thedrug substance are preferably above 50%, more preferably above 70%, mostpreferably above 90%. In a preferred embodiment it is above 95% of thecompound of formula (I) or (IB), or of its salts, solvates or prodrugs.

The compounds of the present invention represented by the abovedescribed formula (I) or (IB) may include enantiomers depending on thepresence of chiral centres or isomers depending on the presence ofmultiple bonds (e.g. Z, E). The single isomers, enantiomers ordiastereoisomers and mixtures thereof fall within the scope of thepresent invention.

The compounds of formula (I) or (IB) defined above can be obtained byavailable synthetic procedures similar to those described in the U.S.Pat. No. 4,337,263 or FR 2 472 564. For example, they can be prepared bycondensing a compound of Formula (II):

in which R₁, R₂ and Y are as defined above in claim 1, with a compoundof Formula (III):

in which X and n are as defined in claims 1 or 2.

The reaction of compounds of formulas (II) and (III) is preferablycarried out at a temperature in the range of 60 to 120° C. in an aproticsolvent, but not limited to, such as dimethylformamide (DMF) in thepresence of an inorganic base, such as K₂CO₃.

A general scheme for synthetizing compounds (II), (I) or (IB) is:

General Scheme of Synthesis

The intermediate compound (II) can also be prepared as described in thebibliography (see L. F. Tietze et al., Synthesis, (11), 1079-1080, 1993;F. Effenberger and W. Hartmann, Chem. Ber., 102(10), 3260-3267, 1969;both cites incorporated here by reference). It can also be prepared byconventional methods, as can be seen in the synthetic examples of thepresent patent application.Compounds of Formula (III) are commercially available or can be preparedby conventional methods.

The obtained reaction products may, if desired, be purified byconventional methods, such as crystallisation and chromatography. Wherethe above described processes for the preparation of compounds of theinvention give rise to mixtures of stereoisomers, these isomers may beseparated by conventional techniques such as preparative chromatography.If there are chiral centers the compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in pharmaceutical composition. In the case of saltsand solvates the additional ionic and solvent moieties must also benon-toxic. The compounds of the invention may present differentpolymorphic forms, it is intended that the invention encompasses allsuch forms.

Another aspect of this invention relates to a method of treating orpreventing a sigma receptor mediated disease which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound as above defined or a pharmaceuticalcomposition thereof. Among the sigma mediated diseases that can betreated are diarrhoea, lipoprotein disorders, metabolic syndrome,treatment of elevated triglyceride levels, chylomicronemia,hyperlipoproteinemia; hyperlipidemia, especially mixed hyperlipidemia;hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemiaincluding both the sporadic and familial disorder (inheritedhypertriglyceridemia), migraine, obesity, arthritis, hypertension,arrhythmia, ulcer, learning, memory and attention deficits, cognitiondisorders, neurodegenerative diseases, demyelinating diseases, addictionto drugs and chemical substances including cocaine, amphetamine, ethanoland nicotine, tardive diskinesia, ischemic stroke, epilepsy, stroke,depression, stress, pain, especially neuropathic pain, inflammatory painor other pain conditions, allodynia and/or hyperalgesia, especiallymechanical allodynia, psychotic condition, schizophrenia; inflammation,autoimmune diseases or cancer; disorders of food ingestion, theregulation of appetite, for the reduction, increase or maintenance ofbody weight, for the prophylaxis and/or treatment of obesity, bulimia,anorexia, cachexia or type II diabetes, preferably type II diabetescaused by obesity. The compounds of the invention can also be employedas pharmacological tool or as anxiolytic or immunosuppressant.

The term “pharmacological tool” refers to the property of compounds ofthe invention through which they are particularly selective ligands forSigma receptors which implies that compound of formula I, described inthis invention, can be used as a model for testing other compounds asSigma ligands, ex. a radioactive ligands being replaced, and can also beused for modeling physiological actions related to Sigma receptors.

The present invention further provides pharmaceutical compositionscomprising a compound of this invention, or a pharmaceuticallyacceptable salt, derivative, prodrug or stereoisomers thereof togetherwith a pharmaceutically acceptable carrier, adjuvant, or vehicle, foradministration to a patient.

Examples of pharmaceutical compositions include any solid (tablets,pills, capsules, granules etc.) or liquid (solutions, suspensions oremulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oralform, either solid or liquid. Suitable dose forms for oraladministration may be tablets, capsules, syrops or solutions and maycontain conventional excipients known in the art such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulfate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art. The tablets may for example be prepared by wet or drygranulation and optionally coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteraladministration, such as sterile solutions, suspensions or lyophilizedproducts in the appropriate unit dosage form. Adequate excipients can beused, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods suchas those described or referred to in the Spanish and US Pharmacopoeiasand similar reference texts.

Administration of the compounds or compositions of the present inventionmay be by any suitable method, such as intravenous infusion, oralpreparations, and intraperitoneal and intravenous administration. Oraladministration is preferred because of the convenience for the patientand the chronic character of the diseases to be treated.

Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 1, 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with otherdrugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition foradministration at the same time or at different time.

The following examples are given only as further illustration even if nolonger part of the invention.

EXAMPLES Example 1 Synthesis of3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridineStep 1A: Synthesis of Acetic Acid N′-(3,4-Dichlorophenyl)hydrazide (V)

N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride(10.0 g, 46.8 mmol) by partitioning the solid between diluted Na₂CO₃solution (10 ml saturated solution and 40 ml water) and AcOEt. Theaqueous layer was extracted two more times with AcOEt, the organicextracts were dried (Na₂SO₄), the solvent was removed in vacuo, and theresidue was taken up in dry toluene (100 ml). To this solution aceticanhydride (4.78 g, 46.8 mmol) was slowly added, and the reaction mixturewas stirred at room temperature for 15 min. Light petroleum (50 ml) wasadded, the mixture was cooled in the refrigerator (−20° C.), and theresulting crystals were collected on a sintered glass funnel and washedwith cold petrol ether. Recrystallization from MeOH yielded (V) (8.30 g,81%) as shiny white crystals, mp 179-182° C. (lit. 168-171° C.). TLCCHCl₃/MeOH 9:1.

MS m/z (%): 222/220/218 (W, 3/22/34), 178 (64), 176 (100), 160 (20), 43(94).

Only the NMR signals of the dominant isomer are given (ratio ca. 9:1):

¹H-NMR (DMSO-d₆): (ppm) 9.69 (d, 11-1, NH—CO, ³J=2.0 Hz), 8.09 (d, 1H,Ph-NH, ³J=2.0 Hz), 7.32 (d, 1H, Ph 1-1-5, ³J (H5, 1-16)=8.8 Hz), 6.83(d, 1H, Ph H-2, ⁴J (H2, H6)=2.5 Hz), 6.66 (dd, 1H, Ph H-6, ⁴3 (H2, 146)2.5 Hz, ³J (H5, H6)=8.8 Hz), 1.90 (s, 31-1, Me).

¹³C-NMR (DMSO-d₆): S (ppm) 169.2 (C═O), 149.6 (Ph C-1), 131.2 (Ph C-3),130.5 (Ph C-5), 119.1 (Ph C-4), 112.9 (Ph C-2*), 112.4 (Ph C-6*), 20.6(Me).

Step 2A: Synthesis of 1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-ol(VI)

To a mixture of (V) (5.0 g, 22.8 mmol) and ethyl acetoacetate (2.97 g22.8 mmol) was slowly added PCl₃ (3.13 g, 22.8 mmol). The mixture waswarmed to 50° C. for 1.5 h, poured into ice water (150 ml), and theresulting precipitate was collected on a sintered glass funnel andrecrystallized from EtOH to yield (VI) (2.29 g, 41%) as white crystals,mp 208-211° C. (lit. 208-209° C.), TLC CHCl₃/MeOH 9:1.

MS m/z (%): 246/244/242 (M+, 11/59/100), 207 (32), 147 (20), 145 (34),111 (20), 109 (23), 75 (20).

¹H-NMR (CDCI3): S (ppm) 11.72 (broad s, 1H, OH), 7.54 (d, 1H, Ph H-5, 3J(H5, H6)=8.5 Hz), 7.48 (d, 1H, Ph 11-2, 4J (H2, H6) 2.5 Hz), 7.26 (dd,1H, Ph H-6, 4J (H2, H6)=2.5 Hz, 3J (H5, H6)=83 Hz), 5.63 (s, 1H, 4-H),2.28 (s, 3H, 5-Me).

¹³C-NMR (CDCl₃): 6 (ppm) 163.1 (Pz C-3), 141.2 (Pz C-5), 137.9 (Ph C-1),133.1 (Ph C-3), 131.4 (Ph C-4), 131.0 (Ph C-5), 126.1 (Ph C-2), 123.6(Ph C-6), 94.5 (Pz C-4), 12.7 (5-Me).

Step 3A. Synthesis of3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole

A mixture of 1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-ol (0.29 g,1.19 mmol), 1-bromo-2-chloroethane (0.2 μl, 2.4 mmol), K₂CO₃ (0.49 g,3.6 mmol) and NaI (0.18 g, 1.19 mmol) in dry dimethylformamide (25 ml)was stirred overnight at room temperature. Solvent was evaporated invacuo and the crude residue was partitioned betweenwater/dichloromethane. The organic extracts were washed with water,dried on Na₂SO₄ and concentrated in vacuo to obtain 0.33 g of an oilycompound, corresponding to a mixture of3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole, andstarting material. Hexane was added to the mixture and stirred for 10min., the unsoluble material, corresponding to unreacted startingcompound, was filtered off, and filtrate evaporated to dryness yielding0.19 g of3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.7 Hz, 1H), 7.3(dd, J=2.5 and 8.7 Hz, 1H), 5.7 (s, 1H), 4.45 (t, J=5.9 Hz, 2H), 3.8 (t,J=5.9 Hz, 2H), 2.3 (s, 3H).

Step 4A. Synthesis of3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine

3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (0.2 g,0.65 mmol), 3-(piperidin-4-yl)-3H-imidazo[4,5-b]pyridine (0.145 g, 0.72mmol), K₂CO₃ (270 mg, 1.96 mmol) and NaI (98 mg, 0.65 mmol) in drydimethylformamide (6 ml) was warmed overnight at 85° C., and then anadditionally 16 hrs at 95° C., in a dry nitrogen atmosphere. Solventswere evaporated in vacuo and the crude residue partitioned inwater/ethyle acetate. The combined organic extracts were washed withwater, dried on Na₂SO₄ and concentrated in vacuo to obtain a yellowcrude oil, which was purified by column chromatography on silica gel(eluent: ethyl acetate 100% and ethyl acetate/MeOH 98/2 and 95/5)yielding 134 mg of3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridineas a white solid with m.p.=104-107° C.

¹H-NMR (CDCl₃) δ ppm: 8.4 (dd, J=1.3 and 4.8 Hz, 1H), 8.2 (s, 1H), 8.1(dd, J=1.3 and 8.1 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.7 Hz,1H), 7.3-7.2 (m+solvent, 2H), 5.7 (s, 1H), 4.75-4.5 (m, 3H), 3.5-3.0 (m,4H), 2.9-2.4 (m, 2H), 2.3 (m+s, 5H), 1.6 (m, 2H).

Example 2 Synthesis of1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amineStep 1. Synthesis ofN-(1-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)pyrrolidin-3-yl)acetamide

3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (0.5 g,1.64 mmol), N-(pyrrolidin-3-yl)acetamide (0.23 g, 1.8 mmol), K₂CO₃ (0.68g, 4.9 mmol) and NaI (245 mg, 1.64 mmol) in dry dimethylformamide (10ml) was warmed overnight at 85° C., and then an additionally 16 hrs at95° C., in a dry nitrogen atmosphere. Solvents were evaporated in vacuoand the crude residue partitioned in water/ethyle acetate. The combinedorganic extracts were washed with water, dried on Na₂SO₄ andconcentrated in vacuo to obtain a yellow crude oil, which was purifiedby column chromatography on silica gel (eluent: ethyl acetate 100% andethyl acetate/MeOH 9/1) yielding 192 mg ofN-(1-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)pyrrolidin-3-yl)acetamideas an oil.

¹H-NMR (DMSO-d₆) δ ppm: 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H),7.3 (dd, J=2.5 and 8.6 Hz, 1H), 5.7 (s, 1H), 4.45 (t, J=5.2 Hz, 2H), 3.1(m, 3H), 2.75 (m, 2H), 2.55 (m, 2H), 2.3 (s, 3H), 1.95 (s, 3H), 1.85 (m,2H).

Step 2. Synthesis of1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine

A solution ofN-(1-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)pyrrolidin-3-yl)acetamide(0.1 g, 0.25 mmol) in water (2 ml) and 6N aqueous solution of HCl (2 ml)was refluxed for 5 hrs. The mixture was basified with 20% aqueoussolution of NaOH and extracted with dichlorometane. The combined organicsolutions was washed with water, dried over Na₂SO₄, filtered andevaporated to dryness yielding 80 mg of1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amineas an oil

¹H-NMR (DMSO-d₆) δ ppm: 7.75 (d, J=2.5 Hz, 1H), 7.7 (d, J=8.7 Hz, 1H),7.5 (dd, J=2.5 and 8.7 Hz, 1H), 5.8 (s, 1H), 4.15 (t, J=5.7 Hz, 2H), 2.7(t, J=5.7 Hz, 2H), 2.65-2.5 (m, 4H), 2.3 (s, 3H), 2.2 (m, 1H), 1.95 (m,1H), 1.35 (m, 1H).

Example 3 Synthesis of Ethyl4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazinecarboxylate Step 1A: Synthesis of Acetic AcidN′-(3,4-Dichlorophenyl)hydrazide (V)

N′-(3,4-Dichlorophenyl)hydrazine was liberated from its hydrochloride(10.0 g, 46.8 mmol) by partitioning the solid between diluted Na₂CO₃solution (10 ml saturated solution and 40 ml water) and AcOEt. Theaqueous layer was extracted two more times with AcOEt, the organicextracts were dried (Na₂SO₄), the solvent was removed in vacuo, and theresidue was taken up in dry toluene (100 ml). To this solution aceticanhydride (4.78 g, 46.8 mmol) was slowly added, and the reaction mixturewas stirred at room temperature for 15 min. Light petroleum (50 ml) wasadded, the mixture was cooled in the refrigerator (−20° C.), and theresulting crystals were collected on a sintered glass funnel and washedwith cold petrol ether. Recrystallization from MeOH yielded (V) (8.30 g,81%) as shiny white crystals, mp 179-182° C. (lit. 168-171° C.). TLCCHCl₃/MeOH 9:1.

MS m/z (%): 222/220/218 (W, 3/22/34), 178 (64), 176 (100), 160 (20), 43(94).

Only the NMR signals of the dominant isomer are given (ratio ca. 9:1):

¹H-NMR (DMSO-d₆): (ppm) 9.69 (d, 11-1, NH—CO, ³J=2.0 Hz), 8.09 (d, 1H,Ph-NH, ³J=2.0 Hz), 7.32 (d, 1H, Ph 1-1-5, ³J (H5, 1-16)=8.8 Hz), 6.83(d, 1H, Ph H-2, ⁴J (H2, H6)=2.5 Hz), 6.66 (dd, 1H, Ph H-6, ⁴3 (H2, 146)2.5 Hz, ³J (H5, H6)=8.8 Hz), 1.90 (s, 31-1, Me).

¹³C-NMR (DMSO-d₆): S (ppm) 169.2 (C═O), 149.6 (Ph C-1), 131.2 (Ph C-3),130.5 (Ph C-5), 119.1 (Ph C-4), 112.9 (Ph C-2*), 112.4 (Ph C-6*), 20.6(Me).

Step 2A: Synthesis of 1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-ol(VI)

To a mixture of (V) (5.0 g, 22.8 mmol) and ethyl acetoacetate (2.97 g22.8 mmol) was slowly added PCl₃ (3.13 g, 22.8 mmol). The mixture waswarmed to 50° C. for 1.5 h, poured into ice water (150 ml), and theresulting precipitate was collected on a sintered glass funnel andrecrystallized from EtOH to yield (VI) (2.29 g, 41%) as white crystals,mp 208-211° C. (lit. 208-209° C.), TLC CHCl₃/MeOH 9:1.

MS m/z (%): 246/244/242 (M+, 11/59/100), 207 (32), 147 (20), 145 (34),111 (20), 109 (23), 75 (20).

¹H-NMR (CDCI3): S (ppm) 11.72 (broad s, 1H, OH), 7.54 (d, 1H, Ph H-5, 3J(H5, H6)=8.5 Hz), 7.48 (d, 1H, Ph 11-2, 4J (H2, H6) −2.5 Hz), 7.26 (dd,1H, Ph H-6, 4J (H2, H6)=2.5 Hz, 3J (H5, H6)=83 Hz), 5.63 (s, 1H, 4-H),2.28 (s, 3H, 5-Me).

¹³C-NMR (CDCl₃): 6 (ppm) 163.1 (Pz C-3), 141.2 (Pz C-5), 137.9 (Ph C-1),133.1 (Ph C-3), 131.4 (Ph C-4), 131.0 (Ph C-5), 126.1 (Ph C-2), 123.6(Ph C-6), 94.5 (Pz C-4), 12.7 (5-Me).

Step 3A. Synthesis of3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole

A mixture of 1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-ol (0.29 g,1.19 mmol), 1-bromo-2-chloroethane (0.2 μl, 2.4 mmol), K₂CO₃ (0.49 g,3.6 mmol) and NaI (0.18 g, 1.19 mmol) in dry dimethylformamide (25 ml)was stirred overnight at room temperature. Solvent was evaporated invacuo and the crude residue was partitioned betweenwater/dichloromethane. The organic extracts were washed with water,dried on Na₂SO₄ and concentrated in vacuo to obtain 0.33 g of an oilycompound, corresponding to a mixture of3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole, andstarting material. Hexane was added to the mixture and stirred for 10min., the unsoluble material, corresponding to unreacted startingcompound, was filtered off, and filtrate evaporated to dryness yielding0.19 g of3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.7 Hz, 1H), 7.3(dd, J=2.5 and 8.7 Hz, 1H), 5.7 (s, 1H), 4.45 (t, J=5.9 Hz, 2H), 3.8 (t,J=5.9 Hz, 2H), 2.3 (s, 3H).

Step 4A. Synthesis of ethyl4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazinecarboxylate

A mixture of3-(2-chloroethoxy)-1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazole (0.2 g,0.65 mmol), ethyl piperazine-1-carboxylate (0.113 g, 0.72 mmol), K₂CO₃(270 mg, 1.96 mmol) and NaI (98 mg, 0.65 mmol) in dry dimethylformamide(6 ml) was warmed overnight at 85° C., and then an additionally 16 hrsat 95° C., in a dry nitrogen atmosphere. Solvents were evaporated invacuo and the crude residue partitioned in water/ethyle acetate. Thecombined organic extracts were washed with water, dried on Na₂SO₄ andconcentrated in vacuo to obtain a crude oil, which was purified bycolumn chromatography on silica gel (ethyl acetate/petroleum ether 8:2)yielding 69 mg of ethyl4-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}piperazinecarboxylate as a colourless oil

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.5 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H),7.3-7.2 (dd+solvent, J=2.5 and 8.6 Hz, 1H), 5.7 (s, 1H), 4.4 (bm, 2H),4.15 (q, J=7.1Hz, 2H), 3.6 (bm, 4H), 2.9-2.6 (bm, 6H), 2.3 (s, 3H), 1.25(t, J=7.1Hz, 3H).

Example 41-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone

Oil. Yield=17%

¹H-NMR (CDCl₃) δ ppm: 7.55 (d, J=2.3 Hz, 1H), 7.5 (d, J=8.6 Hz, 1H),7.3-7.2 (dd+solvent, J=2.3 and 8.6 Hz, 1H), 5.7 (s, 1H), 4.4 (bm, 2H),3.6 (bm, 4H), 2.9-2.6 (bm, 6H), 2.3 (s, 3H), 2.1 (s, 3H).

The following examples 5 to 13 listed in the table were all prepared inan analogous manner based on the preparation described in example 3:

Ex. ¹H-NMR m.p. N^(o) Structure Name δ ppm ° C. MS 5

1-{1-[2-(1-(3,4- Dichlorophenyl)-1H pyrazol-3- yloxy)ethyl] piperidin-4-yl}ethanone oxalate DMSO-d₆: 8.5 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 2.1Hz, 1H), 7.75 (m, 2H), 6.15 (d, J = 2.7 Hz, 1H), 4.5 (t, J = 5.0 Hz,2H), 3.3 (m, 4H), 2.8 (m, 2H), 2.1 (s, 3H), 2.0 (m, 3H), 1.6 (m, 2H).98- 100 381 6

1-{4-[2-(1-(3,4- Dichlo-rophenyl)-1H- pyrazol-3- yloxy)ethyl]pipera-zin-1-yl} ethanone oxalate DMSO-d₆: 8.45 (d, J = 2.6 Hz, 1H), 8.0 (d, J= 2.2 Hz, 1H), 7.75 (m, 2H), 6.1 (d, J = 2.6 Hz, 1H), 4.4 (t, J = 5.4Hz, 2H), 3.5 (m, 4H), 3.0 (m, 2H), 2.7 (m, 4H), 2.0 (s, 3H). 206- 210382 7

1-(1-[2-{1-(2,4- Dichlo-rophenyl)-1H- pyrazol-3- yloxy}ethyl]piperi-din-4-yl)ethanone oxalate DMSO-d₆: 8.0 (d, J = 2.6 Hz, 1H), 7.85 (dd, J= 1.8, 0.7 Hz, 1H), 7.55 (m, 2H), 6.05 (d, J = 2.6 Hz, 1H), 4.4 (t, J =5.1 Hz, 2H), 3.3-3.15 (m + H₂O, 6H), 2.45 (solv + m, 1H), 2.1 (s, 3H),1.9 (m, 2H), 1.6 (m, 2H). 137- 140 381 8

1-(1-(2-(1-(4-Chloro- phenyl)-1H-pyrazol- 3- yloxy)ethyl)piperidin-4-yl)ethanone oxalate DMSO: 8.45 (d, J = 2.6 Hz, 1H), 7.8 (d, J = 8.9Hz, 2H), 7.55 (d, J = 8.9 Hz, 2H), 6.15 (d, J = 2.6 Hz, 1H), 4.5 (t, J =5.1 Hz, 2H), 3.4-3.25 (m, 4H), 2.8 (m, 2H), 2.6 (m, 1H), 2.15 (s, 3H),1.95 (m, 2H), 1.7 (m, 2H). 150- 153 347 9

1-(1-(2-(1-(3,4- Dichlo-rophenyl)-5- methyl-1H-pyrazol-3- yloxy)ethyl)piperidin-4- yl)ethanone oxalate CD₃OD: 7.7 (d, J = 2.4 Hz, 1H),7.65 (d, J = 8.5 Hz, 1H), 7.4 (dd, J = 8.8, 2.4 Hz, 1H), 5.85 (s, 1H),4.55 (m, 2H), 3.65- 3.5 (m, 4H), 3.2-3.1 (m, 2H), 2.8 (m, 1H), 2.35 (s,3H), 2.2 (s, 3H), 2.1 (m, 2H), 1.85 (m, 2H). 158- 165 395 10

1-(4-(4-(1-(3,4- Dichlo-rophenyl)- 4,5-dimethyl-1H- pyrazol-3-yloxy)butyl)piperazin-1- yl)ethanone oxalate DMSO-d₆: 7.7 (d, J = 2.4 Hz, 1H),7.65 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 2.4, 8.8 Hz, 1H), 4.15 (t, J =5.6 Hz, 2H), 3.55 (m, 4H), 2.8 (m, 6H), 2.25 (s, 3H), 2.0 (s, 3H), 1.8(s, 3H), 1.7 (m, 4H). 186- 188 438 11

1-(4-(2-(1-(2,4- Dichlo-rophenyl)-1H- pyrazol-3- yloxy)ethyl)piperazin-1- yl)ethanone oxalate DMSO-d₆: 8.0 (d, J = 2.6 Hz, 1H), 7.85(d, J = 1.9 Hz, 1H), 7.55 (m, 2H), 6.05 (d, J = 2.6 Hz, 1H), 4.3 (t, J =5.4 Hz, 2H), 3.5 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 5.1 Hz, 2H), 2.65 (m,4H), 1.95 (s, 3H). 156- 158 382 12

1-(4-(2-(1-(3,4- Dichlo-rophenyl)- 4,5-dimethyl-1H- pyrazol-3-yloxy)ethyl)piperazin-1- yl)ethanone oxalate (DMSO-d₆: 7.75 (d, J = 2.5 Hz,1H), 7.7 (d, J = 8.8 Hz, 1H), 7.5 (dd, J = 2.5, 8.8 Hz, 1H), 4.35 (t, J= 5.3 Hz, 2H), 3.45- 3.0 (m + H₂O, 4H), 2.95 (m, 2H), 2.65 (m, 4H), 2.25(s, 3H), 1.95 (s, 3H), 1.85 (s, 3H). 180- 184 410 13

1-(4-{4-[1-(3,4- Dichloro-phenyl)-5- methyl-1H-pyrazol-3- yloxy]-butyl}-piperazin-1-yl)- ethanone DMSO-d₆: 7.75 (d, J = 2.5 Hz, 1H), 7.7 (d, J =8.8 Hz, 1H), 7.5 (dd, J = 2.5, 8.8 Hz, 1H), 5.8 (s, 1H), 4.1 (t, J = 5.8Hz, 2H), 3.55 (m, 4H), 2.8 (m, 6H), 2.3 (s, 3H), 2.0 (s, 3H), 1.7 (m,4H) 147- 150 424

Biological Activity

Some representative compounds of the invention were tested for theiractivity as sigma (sigma-1 and sigma-2) inhibitors. The followingprotocols were followed:

Sigma-1

Brain membrane preparation and binding assays for the σ1-receptor wereperformed as described (DeHaven-Hudkins et al., 1992) with somemodifications. In brief, guinea pig brains were homogenized in 10 vols.(w/v) of Tris-HCl 50 mM 0.32 M sucrose, pH 7.4, with a KinematicaPolytron PT 3000 at 15000 r.p.m. for 30 s. The homogenate wascentrifuged at 1000 g for 10 min at 4° C. and the supernatants collectedand centrifuged again at 48000 g for 15 min at 4° C. The pellet wasresuspended in 10 volumes of Tris-HCl buffer (50 mM, pH 7.4), incubatedat 37° C. for 30 min, and centrifuged at 48000 g for 20 min at 4° C.Following this, the pellet was resuspended in fresh Tris-HCl buffer (50mM, pH 7.4) and stored on ice until use.

Each assay tube contained 10 μL of [³H](+)-pentazocine (finalconcentration of 0.5 nM), 900 μL of the tissue suspension to a finalassay volume of 1 mL and a final tissue concentration of approximately30 mg tissue net weight/mL. Non-specific binding was defined by additionof a final concentration of 1 μM haloperidol. All tubes were incubatedat 37° C. for 150 min before termination of the reaction by rapidfiltration over Schleicher & Schuell GF 3362 glass fibre filters[previously soaked in a solution of 0.5% polyethylenimine for at least 1h]. Filters were then washed with four times with 4 mL of cold Tris-HClbuffer (50 mM, pH 7.4). Following addition of scintillation cocktail,the samples were allowed to equilibrate overnight. The amount of boundradioactivity was determined by liquid scintillation spectrometry usinga Wallac Winspectral 1414 liquid scintillation counter. Proteinconcentrations were determined by the method of Lowry et al. (1951).

Sigma-2

Binding studies for σ2-receptor are performed as described (Radesca etal., 1991) with some modifications. In brief, brains from sigma receptortype I (σ1) knockout mice are homogenized in a volume of 10 mL/g tissuenet weight of ice-cold 10 mM Tris-HCl, pH 7.4, containing 320 mM sucrose(Tris-sucrose buffer) with a Potter-Elvehjem homogenizer (10 strokes at500 r.p.m.) The homogenates are then centrifuged at 1000 g for 10 min at4° C., and the supernatants are saved. The pellets are resuspended byvortexing in 2 mL/g ice-cold Tris-sucrose buffer and centrifuged againat 1000 g for 10 min. The combined 1000 g supernatants are centrifugedat 31000 g for 15 min at 4° C. The pellets are resuspended by vortexingin 3 mL/g 10 mM Tris-HCl, pH 7.4, and the suspension is kept at 25° C.for 15 min. Following centrifugation at 31000 g for 15 min, the pelletsare resuspended by gentle Potter Elvehjem homogenization to a volume of1.53 mL/g in 10 mM Tris-HCl pH 7.4.

The assay tubes contain 10 μL of [³H]-DTG (final concentration of 3 nM),400 μL of the tissue suspension (5.3 mL/g in 50 mM Tris-HCl, pH 8.0) toa final assay volume of 0.5 mL. Non-specific binding is defined byaddition of a final concentration of 1 μM haloperidol. All tubes areincubated at 25° C. for 120 min before termination of the reaction byrapid filtration over Schleicher & Schuell GF 3362 glass fibre filters[previously soaked in a solution of 0.5% polyethylenimine for at least 1h]. Filters are washed three times with 5 mL volumes of cold Tris-HClbuffer (10 mM, pH 8.0). Following addition of scintillation cocktailsamples are allowed to equilibrate overnight. The amount of boundradioactivity is determined by liquid scintillation spectrometry using aWallac Winspectral 1414 liquid scintillation counter. Proteinconcentrations are determined by the method of Lowry et al. (1951).

REFERENCES

-   DeHaven-Hudkins, D. L., L. C. Fleissner, and F. Y. Ford-Rice, 1992,    “Characterization of the binding of [³H](+)pentazocine to σ    recognition sites in guinea pig brain”, Eur. J. Pharmacol. 227,    371-378.-   Radesca, L., W. D. Bowen, and L. Di Paolo, B. R. de Costa, 1991,    Synthesis and Receptor Binding of Enantiomeric N-Substituted    cis-N-[2-(3,4-Dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamines    as High-Affinity σ Receptor Ligands, J. Med. Chem. 34, 3065-3074.-   Langa, F., Codony X., Tovar V., Lavado A., Giménez E., Cozar P.,    Cantero M., Dordal A., Hernández E., Pérez R., Monroy X., Zamanillo    D., Guitart X., Montoliu Ll., 2003, Generation and phenotypic    analysis of sigma receptor type I (Sigma1) knockout mice, European    Journal of Neuroscience, Vol. 18, 2188-2196.-   Lowry, O. H., N. J. Rosebrough, A. L. Farr, and R. J. Randall, 1951,    Protein measurement with the Folin phenol reagent, J. Biol. Chem.,    193, 265.

Some of the results obtained for the Sigma-1 Receptor are shown in table(I).

TABLE (I) % Binding σ1 % Binding σ1 K_(i) Example 10⁻⁷M 10⁻⁸M [nM] 194.4 49.4 2 90.7 53.2 3 99.5 58.4 4 99.4 82.5 5 1.3 ± 0.4 6 4.2 7 1.5 81.3 9 8.3

In-Vivo-Experiments Using Von Frey Filaments in a Model ofCapsaicine-Induced Allodynia:

This model is described in detail in the experimental part of WO2006/010587 A1, examples 1 and 2, the description being included here byreference. Capsaicin is thereby injected into experimental animals toproduce acute pain followed by allodynia.

Briefly after habituation mice were first treated with the test-compound(or not in controls). Then capsaicin (1% DMSO) is injected into theirpaw resulting in developing pain in the effected paw. The effected pawis then treated with a mechanical stimulus and the latency time beforethe paw is withdrawn is measured.

The compound according to example 6 was tested and 77% analgesia wasachieved at a capsaicin concentration of 16 mg.

1-26. (canceled)
 27. A method of treating or preventing a sigma receptormediated disease or condition, said method comprising administering to apatient in need of such a treatment or prevention a therapeuticallyeffective amount of a compound of formula (I):

wherein R₁ is selected from the group formed by hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted alkenyl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR₈,—C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉,—NO₂, —N═CR₈R₉, or halogen; R₂ is selected from the group formed byhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN,—OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, orhalogen; Y is selected from substituted or unsubstituted phenyl ornaphthyl; X is selected from: —CH₂-Het-CHR_(x)—, —CH₂—CHR_(x)-Het-,-Het-CH₂—CHR_(x)—, —CH₂—CH₂—CHR_(x)—, or —CH₂—CHR_(x)—CH₂—, with Hetbeing NH, S or O, —CHR_(x)— being

 wherein R₅ and R₆, identical or different, represent a hydrogen atom;an optionally substituted C₁₋₄ alkyl group; an optionally substitutedaryl group; an optionally substituted heteroaryl group; a C₁₋₄ alkoxygroup; a benzyl group; a phenethyl group; or form, together with theirbridging nitrogen atom, an optionally substituted heteroaryl group whichis optionally condensed to other, optionally at least one heteroatomcontaining mono- or polycyclic ring system which is optionally at leastmono-substituted; or X is selected from: —CH₂-Het-CHR_(x)—,—CH₂—CHR_(x)-Het-, -Het-CH₂—CHR_(x)—, —CH₂—CH₂—CHR_(x)—,—CH₂—CHR_(x)—CH₂—, —CH₂—CH₂—NR_(x)—, or —CH₂—NR_(x)—CH₂—, with Het beingNH, S or O, R_(x), being a —(C═O)—R¹⁰; or a —(C═O)—O—R¹¹ group; whereinR¹⁰ and R¹¹ independently represent a hydrogen atom; a saturated orunsaturated, optionally at least mono-substituted C₁₋₆ alkyl group; anoptionally at least mono-substituted aryl group; an optionally at leastmono-substituted heteroaryl group; an optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining cycloalkyl group; a saturated or unsaturated, optionally atleast mono-substituted C₁₋₆ alkyl-aryl group; a saturated orunsaturated, optionally at least mono-substituted C₁₋₆ alkyl-heteroarylgroup; or a saturated or unsaturated, optionally at leastmono-substituted C₁₋₆ alkyl-cycloalkyl group wherein the cycloalkylgroup contains optionally at least one heteroatom as ring member; n isselected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1, 2 or 3; R₈ and R₉ areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclyl, or halogen; optionally in form of a racematein any mixing ratio, or a corresponding salt thereof.
 28. The methodaccording to claim 27, wherein the compound of formula I comprises acompound of formula IB:

wherein R₁ is selected from the group formed by hydrogen; substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,—C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2,—N═CR₈R₉ or halogen, R₂ is selected from the group formed by hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,—OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;R₃ and R₄ are independently selected from the group formed by hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,—OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2, —N═CR₈R₉, or halogen,or together with the phenyl ring to which they are attached they form asubstituted or unsubstituted naphthyl ring, X is selected from:—CH₂-Het-CHR_(x)—, —CH₂—CHR_(x)-Het-, -Het-CH₂—CHR_(x)—,—CH₂—CH₂—CHR_(x)—, or —CH₂—CHR_(x)—CH₂—, with Het being NH, S or O,—CHR_(x)— being

 wherein R₅ and R₆, identical or different, represent a hydrogen atom;an optionally substituted C₁₋₄ alkyl group; an optionally substitutedaryl group; an optionally substituted heteroaryl group; a C₁₋₄ alkoxygroup; a benzyl group; a phenethyl group; or form, together with theirbridging nitrogen atom, an optionally substituted heteroaryl group whichis optionally condensed to other, optionally at least one heteroatomcontaining mono- or polycyclic ring system which is optionally at leastmono-substituted; or X is selected from: —CH₂-Het-CHR_(x)—,—CH₂—CHR_(x)-Het-, -Het-CH₂—CHR_(x)—, —CH₂—CH₂—CHR_(x)—,—CH₂—CHR_(x)—CH₂—, —CH₂—CH₂—NR_(x)—, or —CH₂—NR_(x)—CH₂—, with Het beingNH, S or O, R_(x) being a —(C═O)—R¹⁰; or a —(C═O)—O—R¹¹ group; whereinR¹⁰ and R¹¹ independently represent a hydrogen atom; a saturated orunsaturated, optionally at least mono-substituted C₁₋₆ alkyl group; anoptionally at least mono-substituted aryl group; an optionally at leastmono-substituted heteroaryl group; an optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining cycloalkyl group; a saturated or unsaturated, optionally atleast mono-substituted C₁₋₆ alkyl-aryl group; a saturated orunsaturated, optionally at least mono-substituted C₁₋₆ alkyl-heteroarylgroup; or a saturated or unsaturated, optionally at leastmono-substituted C₁₋₆ alkyl-cycloalkyl group wherein the cycloalkylgroup contains optionally at least one heteroatom as ring member; n isselected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1, 2 or 3; R₈ and R₉ areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclyl, or halogen; optionally in form of a racematein any mixing ratio, or a corresponding salt thereof.
 29. The methodaccording to claim 27, wherein the compound of formula I comprises:

wherein R₁ is selected from the group formed by hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted alkenyl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR₈,—C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉,—NO₂, —N═CR₈R₉, or halogen; R₂ is selected from the group formed byhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN,—OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, orhalogen; Y is selected from substituted or unsubstituted phenyl ornaphtyl; X is selected from: —CH₂-Het-CHR_(x)—, —CH₂—CHR_(x)-Het-,-Het-CH₂—CHR_(x)—, —CH₂—CH₂—CHR_(x)—, or —CH₂—CHR_(x)—CH₂—, with Hetbeing NH, S or O, —CHR_(x)— being

 wherein R₅ and R₆, identical or different, represent a hydrogen atom;an optionally substituted C₁₋₄ alkyl group; an optionally substitutedaryl group; an optionally substituted heteroaryl group; a C₁₋₄ alkoxygroup; a benzyl group; a phenethyl group; or form, together with theirbridging nitrogen atom, an optionally substituted heteroaryl group whichis optionally condensed to other, optionally at least one heteroatomcontaining mono- or polycyclic ring system which is optionally at leastmono-substituted; n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1,2, or 3; R₈ and R₉ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl, orhalogen; optionally in form of a racemate in any mixing ratio, or acorresponding salt thereof.
 30. The method according to claim 28,wherein the compound of formula IB comprises:

wherein R₁ is selected from the group formed by hydrogen; substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,—C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2,—N═CR₈R₉ or halogen, R₂ is selected from the group formed by hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,—OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;R₃ and R₄ are independently selected from the group formed by hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,—OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2, —N═CR₈R₉, or halogen,or together with the phenyl ring to which they are attached they form asubstituted or unsubstituted naphthyl ring, X is selected from:—CH₂-Het-CHR_(x)—, —CH₂—CHR_(x)-Het-, -Het-CH₂—CHR_(x)—,—CH₂—CH₂—CHR_(x)—, or —CH₂—CHR_(x)—CH₂—, with Het being NH, S or O,—CHR_(x)— being

 with R₅ and R₆, identical or different, represent a hydrogen atom; anoptionally substituted C₁₋₄ alkyl group; an optionally substituted arylgroup; an optionally substituted heteroaryl group; a C₁₋₄ alkoxy group;a benzyl group; a phenethyl group; or form, together with their bridgingnitrogen atom, an optionally substituted heteroaryl group which isoptionally condensed to other, optionally at least one heteroatomcontaining mono- or polycyclic ring system which is optionally at leastmono-substituted; n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1, 2or 3; R₈ and R₉ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl, orhalogen; optionally in form of a racemate in any mixing ratio, or acorresponding salt thereof.
 31. The method according to claim 27,wherein the compound of formula I comprises:

wherein R₁ is selected from the group formed by hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted alkenyl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR₈,—C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉,—NO₂, —N═CR₈R₉, or halogen; R₂ is selected from the group formed byhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN,—OR₈, —OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, orhalogen; Y is selected from substituted or unsubstituted phenyl ornaphtyl; X is selected from: —CH₂-Het-CHR_(x)—, —CH₂—CHR_(x)-Het-,-Het-CH₂—CHR_(x)—, —CH₂—CH₂—CHR_(x)—, —CH₂—CHR_(x)—CH₂—,—CH₂—CH₂—NR_(x)—, or —CH₂—NR_(x)—CH₂—, with Het being NH, S or O, R_(x)being a —(C═O)—R¹⁰; or a —(C═O)—O—R¹¹ group; and R¹⁰ and R¹¹independently represent a hydrogen atom; a saturated or unsaturated,optionally at least mono-substituted C₁₋₆ alkyl group; an optionally atleast mono-substituted aryl group; an optionally at leastmono-substituted heteroaryl group; an optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining cycloalkyl group; a saturated or unsaturated, optionally atleast mono-substituted C₁₋₆ alkyl-aryl group; a saturated orunsaturated, optionally at least mono-substituted C₁₋₆ alkyl-heteroarylgroup; or a saturated or unsaturated, optionally at leastmono-substituted C₁₋₆ alkyl-cycloalkyl group wherein the cycloalkylgroup contains optionally at least one heteroatom as ring member; n isselected from 1, 2, 3, 4, 5, 6, 7 or 8; t is 1, 2 or 3; R₈ and R₉ areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclyl, or halogen; optionally in form of a racematein any mixing ratio, or a corresponding salt thereof.
 32. The methodaccording to claim 28, wherein the compound of formula IB comprises:

wherein R₁ is selected from the group formed by hydrogen; substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, —COR₈, —C(O)OR₈,—C(O)NR₈R₉—C═NR₈, —CN, —OR₈, —OC(O)R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2,—N═CR₈R₉ or halogen, R₂ is selected from the group formed by hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,—OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO₂, —N═CR₈R₉, or halogen;R₃ and R₄ are independently selected from the group formed by hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclylalkyl, —COR₈, —C(O)OR₈, —C(O)NR₈R₉—C═NR₈, —CN, —OR₈,—OC(O)R₈, —S(O)_(t)—R₈, —NR₈R₉, —NR₈C(O)R₉, —NO2, —N═CR₈R₉, or halogen,or together with the phenyl ring to which they are attached they form asubstituted or unsubstituted naphthyl ring, X is selected from:—CH₂-Het-CHR_(x)—, —CH₂—CHR_(x)-Het-, -Het-CH₂—CHR_(x)—,—CH₂—CH₂—CHR_(x)—, —CH₂—CHR_(x)—CH₂—, —CH₂—CH₂—NR_(x)—, or—CH₂—NR_(x)—CH₂—, with Het being NH, S or O, R_(x) being a —(C═O)—R¹⁰;or a —(C═O)—O—R¹¹ group; and R¹⁰ and R¹¹ independently represent ahydrogen atom; a saturated or unsaturated, optionally at leastmono-substituted C₁₋₆ alkyl group; an optionally at leastmono-substituted aryl group; an optionally at least mono-substitutedheteroaryl group; an optionally at least mono-substituted, optionally atleast one heteroatom as ring member containing cycloalkyl group; asaturated or unsaturated, optionally at least mono-substituted C₁₋₆alkyl-aryl group; a saturated or unsaturated, optionally at leastmono-substituted C₁₋₆ alkyl-heteroaryl group; or a saturated orunsaturated, optionally at least mono-substituted C₁₋₆ alkyl-cycloalkylgroup wherein the cycloalkyl group contains optionally at least oneheteroatom as ring member; n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;t is 1, 2 or 3; R₈ and R₉ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl, orhalogen; optionally in form of a racemate in any mixing ratio, or acorresponding salt thereof.
 33. The method according to claim 27,wherein the compound of formula I is characterized in that R₁ isselected from H, halogen, —COR₈, or substituted or unsubstituted alkyl,preferably it is selected from H, Cl, methyl or acetyl.
 34. The methodaccording to claim 27, wherein the compound of formula I ischaracterized in that R₁ is hydrogen.
 35. The method according to claim27, wherein the compound of formula I is characterized in that R₂ is H,aryl, C(O)OR₈ or alkyl, preferably methyl, iso-propyl, phenyl,C(O)O—C₂H₅ or H.
 36. The method according to claim 28, wherein thecompound of formula IB is characterized in that R₃ and R₄ are situatedin the meta and para positions of the phenyl group.
 37. The methodaccording to claim 28, wherein the compound of formula IB ischaracterized in that R₃ and R₄ are independently selected from halogen,hydrogen, alkoxy, or substituted or unsubstituted alkyl, more preferablyselected from hydrogen, halogen, Cl, methoxy or haloalkyl.
 38. Themethod according to claim 28, wherein the compound of formula IB ischaracterized in that R₃ and R₄ together with the phenyl ring to whichthey are attached form a substituted or unsubstituted naphthyl-radical.39. The method according to claim 27, wherein the compound of formula Iis characterized in that n is selected from 2, 3, and
 4. 40. The methodaccording to claim 27, wherein the compound of formula I ischaracterized in that X is selected from the group consisting of—CH₂—CH₂—CHR_(x)—, and —CH₂—CHR_(x)—CH₂—.
 41. The method according toclaim 27, wherein the compound of formula I is characterized in that R₅and R₆ are selected from hydrogen or alkyl or form, together with theirbridging nitrogen atom, an optionally substituted heteroaryl group whichis optionally condensed to other, optionally at least one heteroatomcontaining mono- or polycyclic ring system which is optionally at leastmono-substituted, especially an indazole or an 1H-indazole.
 42. Themethod according to claim 27, wherein the compound of formula I ischaracterized in that the compound is selected from the group consistingof:3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridine,and3-{1-[2-(1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}-3H-imidazo[4,5-b]pyridineoxalate, optionally in form of a racemate in any mixing ratio, or acorresponding salt thereof.
 43. The method according to claim 27,wherein the compound of formula I is characterized in that X is selectedfrom the group consisting of —CH₂—CH₂—NR_(x)—, and —CH₂—NR_(x)—CH₂—. 44.The method according to claim 27, wherein the compound of formula I ischaracterized in that R₁₀ and R₁₁ are independently selected fromhydrogen or alkyl.
 45. The method according to claim 27, wherein thecompound of formula I is characterized in that the compound is selectedfrom the group consisting of1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone,1-(4-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanoneoxalate,1-{1-[2-(1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}ethanone,1-{1-[2-(1-(3,4-Dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl]piperidin-4-yl}ethanoneoxalate,1-{4-[2-(1-(3,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy)ethyl]piperazin-1-yl}ethanone,1-{4-[2-(1-(3,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy)ethyl]piperazin-1-yl}ethanoneoxalate,1-(1-[2-{1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy}ethyl]piperidin-4-yl)ethanone,1-(1-[2-{1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy}ethyl]piperidin-4-yl)ethanoneoxalate,1-(1-(2-(1-(4-Chloro-phenyl)-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanone,1-(1-(2-(1-(4-Chloro-phenyl)-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanoneoxalate,1-(1-(2-(1-(3,4-Dichlo-rophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanone,1-(1-(2-(1-(3,4-Dichlo-rophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperidin-4-yl)ethanoneoxalate,1-(4-(4-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)butyl)piperazin-1-yl)ethanone,1-(4-(4-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)butyl)piperazin-1-yl)ethanoneoxalate,1-(4-(2-(1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone,1-(4-(2-(1-(2,4-Dichlo-rophenyl)-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanoneoxalate,1-(4-(2-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone,1-(4-(2-(1-(3,4-Dichlo-rophenyl)-4,5-dimethyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanoneoxalate,1-(4-{4-[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-3-yloxy]-butyl}-piperazin-1-yl)-ethanone,and1-(4-{4-[1-(3,4-Dichloro-phenyl)-5-methyl-1H-pyrazol-3-yloxy]-butyl}-piperazin-1-yl)-ethanoneoxalate; optionally in form of a racemate in any mixing ratio, or acorresponding salt thereof.
 46. The method according to claim 27,wherein the compound of formula I is provided as a pharmaceuticalcomposition which comprises a compound as defined in claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant or vehicle.
 47. The method according toclaim 27, wherein the disease is diarrhoea, lipoprotein disorders,metabolic syndrome, treatment of elevated triglyceride levels,chylomicronemia, hyperlipoproteinemia; hyperlipidemia, especially mixedhyperlipidemia; hypercholesterolemia, dysbetalipoproteinemia,hypertriglyceridemia including both the sporadic and familial disorder(inherited hypertriglyceridemia), migraine, obesity, arthritis,hypertension, arrhythmia, ulcer, learning, memory and attentiondeficits, cognition disorders, neurodegenerative diseases, demyelinatingdiseases, addiction to drugs and chemical substances including cocaine,amphetamine, ethanol and nicotine, tardive diskinesia, ischemic stroke,epilepsy, stroke, depression, stress, psychotic condition,schizophrenia; inflammation, autoimmune diseases or cancer; disorders offood ingestion, the regulation of appetite, for the reduction, increaseor maintenance of body weight, for the prophylaxis and/or treatment ofobesity, bulimia, anorexia, cachexia or type II diabetes, preferablytype II diabetes caused by obesity.
 48. The method according to claim27, wherein the disease is pain, especially neuropathic pain,inflammatory pain or other pain conditions, allodynia and/orhyperalgesia, especially mechanical allodynia.